Supplementary Figure S6 from Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer

Kemp, Samantha B.; Cheng, Noah; Markosyan, Nune; Sor, Rina; Kim, Il-Kyu; Hallin, Jill; Shoush, Jason; Quinones, Liz; Brown, Natalie V.; Bassett, Jared B.; Joshi, Nikhil; Yuan, Salina; Smith, Molly; Vostrejs, William P.; Perez-Vale, Kia Z.; Kahn, Benjamin; Mo, Feiyan; Donahue, Timothy R.; Radu, Caius G.; Clendenin, Cynthia; Christensen, James G.; Vonderheide, Robert H.; Stanger, Ben Z.

doi:10.1158/2159-8290.22541970.v1

Supplementary Figure S6 from Efficacy of a Small-Molecule Inhibitor of Kras<sup>G12D</sup> in Immunocompetent Models of Pancreatic Cancer

https://doi.org/10.1158/2159-8290.22541970

journal contribution

posted on 2023-04-04, 00:23 authored by Samantha B. Kemp, Noah Cheng, Nune Markosyan, Rina Sor, Il-Kyu Kim, Jill Hallin, Jason Shoush, Liz Quinones, Natalie V. Brown, Jared B. Bassett, Nikhil Joshi, Salina Yuan, Molly Smith, William P. Vostrejs, Kia Z. Perez-Vale, Benjamin Kahn, Feiyan Mo, Timothy R. Donahue, Caius G. Radu, Cynthia Clendenin, James G. Christensen, Robert H. Vonderheide, Ben Z. Stanger

<p>KRASG12D inhibition alters the tumor immune microenvironment</p>

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Cancer Research Institute (CRI)

Parker Institute for Cancer Immunotherapy (Parker Institute)

Abramson Family Cancer Research Institute (AFCRI)

Penn Pancreatic Cancer Research Center

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DOI - Is supplement to Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer

ARTICLE ABSTRACT

Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC.See related commentary by Redding and Grabocka, p. 260.This article is highlighted in the In This Issue feature, p. 247

Supplementary Figure S6 from Efficacy of a Small-Molecule Inhibitor of Kras<sup>G12D</sup> in Immunocompetent Models of Pancreatic Cancer

Funding

National Cancer Institute (NCI)

Cancer Research Institute (CRI)

Parker Institute for Cancer Immunotherapy (Parker Institute)

Abramson Family Cancer Research Institute (AFCRI)

Penn Pancreatic Cancer Research Center

History

Related Materials

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